Abstract
The ABL1 proto-oncogene encodes a cytoplasmic and nuclear protein tyrosine kinase (c-Abl) that has been implicated in processes of cell differentiation, cell division, cell adhesion and stress response1–4. Alterations of ABL1 by chromosomal rearrangement or viral transduction can lead to malignant transformation5,6. Activity of the c-Abl protein is negatively regulated by its SH3 domain through an unknown mechanism, and deletion of the SH3 domain turns ABL1 into an oncogene7–10. We present evidence for an intramolecular inhibitory interaction of the SH3 domain with the catalytic domain and with the linker between the SH2 and catalytic domain (SH2-CD linker). Site-directed mutations in each of these three elements activate c-Abl. Mutations in the linker cause a conformational change of the molecule and increase binding of the SH3 domain to peptide ligands. Individual mutation of two charged residues in the SH3 and catalytic domain activates c-Abl, while inhibition is restored in the double reciprocal mutant. We propose that regulators of c-Abl will have opposite effects on its activity depending on their ability to favour or disrupt these intramolecular interactions.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
References
Wang, J.Y.J. Abl tyrosine kinase in signal transduction and cell-cycle regulation. Curr. Opin. Gen. Dev. 3, 35–43 (1993).
Kharbanda, S. et al. Activation of the c-Abl tyrosine kinase in the stress response to DMA-damaging agents. Nature 376, 785–788 (1995).
Liu, Z.-G. et al. Three distinct signalling responses by murine fibroblasts to genotoxic stress. Nature 384, 273–276 (1996).
Lewis, J.M., Baskaran, R., Taagepera, S., Schwartz, M.A. & Wang, J.Y. Integrin regulation of c-Abl tyrosine kinase activity and cytoplasmic-nuclear transport. Proc. Natl. Acad. Sci. USA 93, 15174–15179 (1996).
Kurzrock, R., Guttermann, J. & Talpaz, M. The molecular genetics of Philadelphia chromosome-positive leukemias. N. Engl. J. Med. 319, 990–998 (1988).
Rosenberg, N. & Witte, O.N. The viral and cellular forms of the Abelson oncogene. Adv. Virus Res. 35, 39–81 (1988).
Franz, W.M., Berger, P. & Wang, J.Y.J. Deletion of an N-terminal regulatory domain of the c-Abl tyrosine kinase activates its oncogenic potential. EMBO J. 8, 137–147 (1989).
Jackson, P. & Baltimore, D. N-terminal mutations activate the leukemogenic potential of the myristylated form of c-abl. EMBO J. 8, 449–456 (1989).
Pendergast, A.M. et al. Evidence for regulation of the human ABL tyrosine kinase by a cellular inhibitor. Proc. Natl. Acad. Ad. USA 88, 5927–5931 (1991).
Mayer, B.J. & Baltimore, D. Mutagenic analysis of the roles of SH2 and SH3 domains in regulation of the Abl tyrosine kinase. Mol. Cell. Biol. 14, 2883–2894 (1994).
Xu, W., Harrison, S.C. & Eck, M.J. Three-dimensional structure of the tyrosine kinase c-Src. Nature 385, 595–602 (1997).
Sicheri, F., Moarefi, I. & Kuriyan, J. Crystal structure of the Src family tyrosine kinase Hck. Nature 385, 602–609 (1997).
Williams, J.C. et al. The 2.35 Å crystal structure of the inactivated form of chicken Src: a dynamic molecule with multiple regulatory interactions. J. Mol. Biol. 274, 757–775 (1997).
Lim, W.A., Richards, D.M. & Fox, D.O. Structural determinants of peptide-binding orientation and of sequence specificity in SH3 domains. Nature 372, 375–379 (1994).
Superti-Furga, G. & Courtneidge, S.A. Structure-function relationships in Src family and related protein tyrosine kinases. Bioessays 17, 321–330 (1995).
Erpel, T., Superti-Furga, G. & Courtneidge, S.A. Mutational analysis of the Src SH3 domain: the same residues of the ligand binding surface are important for intra-and inter-molecular interactions. EMBO J. 14, 963–975 (1995).
Gonfloni, S. et al. The role of the linker between the SH2 domain and catalytic domain in the regulation and function of Src. EMBO J. 16, 7261–7271 (1997).
Goga, A. et al. Oncogenic activation of c-Abl by mutation within its last exon. Mol. Cell. Biol. 13, 4967–4975 (1993).
Alexandropoulos, K. & Baltimore, D. Coordinate activation of c-Src by SH3 and SH2 binding sites on a novel, p130Cas-related protein, Sin. Genes Dev. 10, 1341–1355 (1996).
Renshaw, M.W., McWhirter, J.R. & Wang, J.Y.J. The human leukemia oncogene bcr-abl abrogates the anchorage requirement but not the growth factor requirement for proliferation. Mol. Cell. Biol. 15, 1286–1293 (1995).
Renshaw, M.W., Kipreos, E., Albrecht, M.R. & Wang, J.Y.J. Oncogenic v-Abl tyrosine kinase can inhibit or stimulate growth, depending on the cell context. EMBO J. 11, 3941–3951 (1992).
MacAuley, A. & Cooper, J.A. Structural differences between repressed and derepressed forms of p60c-src. Mol. Cell. Biol. 9, 2648–2656 (1989).
Pisabarro, M.T. & Serrano, L. Rational design of specific high-affinity peptide ligands for the Abl SH3 domain. Biochemistry 35, 10634–10640 (1996).
Reynolds, C.H. et al. Comparison of baculovirus-expressed c-Abl and BCR/ABL protein tyrosine kinases. Biochim. Biophys. Acta 1181, 122–130 (1993).
Walkenhorst, J., Goga, A., Witte, O.N. & Superti-Furga, G. Analysis of human c-Abl tyrosine kinase activity and regulation in S. pombe. Oncogene 12, 1513–1520 (1996).
Dai, Z. & Pendergast, A.M., Abi-2, a novel SH3-containing protein interacts with the c-Abl tyrosine kinase and modulates c-Abl transforming activity. Genes Dev. 9, 2596–2582 (1995).
Shi, Y ., Ålin, K. & Goff, S.P. Abl-interactor-1, a novel SH3 protein binding to the carboxy-terminal portion of the Abl protein, suppresses v-abl transforming activity. Genes Dev. 9, 2583–2597 (1995).
Wen, S.-T. & Van Etten, R.A. The PAG gene product, a stress-induced protein with antioxidant properties, is an Abl SH3-binding protein and a physiological inhibitor of c-Abl tyrosine kinase activity. Genes Dev. 11, 2456–2467 (1997).
Zhu, J. & Shore, S.K. c-Abl tyrosine kinase activity is regulated by association with a novel SH3-domain-binding protein. Mol. Cell. Biol. 16, 7054–7062 (1996).
Ausubel, F.M. et al. Nonisotrpic assays for reporter gene activity, in Current protocols in molecular biology. Unit 9.7B (John Wiley and Sons, New York, 1987).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Barilá, D., Superti-Furga, G. An intramolecular SH3-domain interaction regulates c-Abl activity. Nat Genet 18, 280–282 (1998). https://doi.org/10.1038/ng0398-280
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng0398-280